Using the technique of inter-(simple sequence repeat) PCR, we have shown that genomic destabilization in human sporadic colorectal cancer begins very early in progression and is extensive, with an estimate of around ten thousand events per tumor cell. We hypothesize that this rampant instability may be the essence of this malignancy, facilitating vastly accelerated somatic evolution, which through natural selection evolves to the proliferating, invading, evolving mass of cells known as cancer. But what are these genomic events arising out of genomic instability, which we are detecting? By what mechanisms do they occur? Are they truly relevant? By characterizing events detected by inter-(simple sequence repeat) PCR, we intend to answer these questions. Molecular characterization will point to mechanisms, and localization and sequencing will test randomness. Colorectal tumors are heterogeneous, but how extensive is this at the genome level? Are cells with severely disrupted genomes only dead end side branches in the tumor progression pathway? By comparing the genomic damage in multiple microsamples in comparison to that of macrosamples, we will evaluate if lineages with severely disrupted genomes exist and continue to progress. What is the relationship between MLH3 mutation and non- microsatellite instability in sporadic colorectal cancer. We have published evidence that MLH3 may play an important role in intrachromosomal instability in sporadic colorectal cancer. This work will be tested and developed. These studies should allow us to develop a clearer picture of how genomic instability relates to human colorectal tumor progression, how it relates to tumor heterogeneity, and how it arises mechanistically.